Both platinum(II) and platinum(IV) compounds have been recognized to be useful as cancer chemotherapeutics since Rosenberg's (and colleagues') discovery in 1965 (Rosenberg, 1965). Cisplatin, cis-diaminodichloroplatinum(II), FDA-approved in 1978; and carboplatin, cis-diaminocyclobutane-1,1-dicarboxylic acid platinum(II), FDA-approved in 1989, continue to be widely prescribed. Both of these platinum(II) compounds form DNA-adducts, primarily responsible for their anticancer properties. Dose-limiting side effects include nephrotoxicity, ototoxicity, gastrointestinal toxicity, neurotoxicity and bone marrow damage; carboplatin exhibits comparatively reduced toxicities, while transplatin (the trans-diaminodichloroplatinum(II) isomer) has been demonstrated to be relatively ineffective for cancer (Kelland, 1994; Singh, 1988). Cisplatin and its analogues have been useful in treatments of testicular, prostate, ovarian, bladder, head and neck, cervical, lung, stomach, and pancreatic cancers. While some undesired effects are reversible, myelosuppression (leukopenia and thrombocytopenia) as well as inherent and acquired resistances are more prohibitive. Newer platinum complexes have been explored, intending to circumvent resistance and reduce toxicities (Kelland, 1999). The approach has largely been towards Pt(IV) prodrugs, reducing to their active Pt(II) analogues through biological reductants, then forming DNA adducts (Hall, 2004); platinum-DNA adducts consistently account for these antitumor activities. Since toxicities have partly been associated with Pt(II)-protein and -sulfur conjugates (Townsend, 2002), Pt(IV) prodrugs can serve to limit these by minimizing serum exposure to the active (+2) form.
Some platinum(IV) complexes, however, have demonstrated unique interactions. Among these are inhibitors of Signal Transducers and Activators of Transcription (STAT) proteins, cytoplasmic transcription factors controlling cellular proliferation, differentiation, development, inflammation, and apoptosis in response to cytokines and growth factors (Turkson, 2004; Kortylewski, 2005). STATs are activated by tyrosine phosphorylation leading to dimerization; dimers translocate to the nucleus, bind to specific DNA response elements, and activate gene expression. Seven STATs have been identified in humans. Of these, STAT3 aberrant activity has been detected in both solid and hematological human tumors (Yu, 2004; Bromberg, 2001; Bromberg, 2002) and describes a new therapeutic target as well as a novel platinum mechanism.
Recently, another novel cellular target has been identified, selective to a subgroup of platinum(IV) complexes. This target is localized within cellular membranes—as opposed to nucleotides or the nucleus—and is composed of caveolae and lipid rafts, identified targets for multiple diseases and key regulators of numerous cellular processes (Tamaskar, 2008; Frank, 2007; Medina, 2007; Silva, 2007; Jasmin, 2006; Medina, 2006; Fine, 2005; Williams, 2005; Williams, 2004; Dhillon, 2003).
Caveolin proteins act either as positive or negative regulators for primary tumor growth, depending upon cell type (Williams, 2005), and thus determine potential therapeutic benefit of platinum(IV) compounds Tumor metastasis, on the other hand, largely relates to reduced caveolin-1 activity together with increased secretions of invasive matrix metalloproteinases-2 and -9 (Williams, 2005) such that therapeutic benefits as a cotherapy for reducing metastasis may be useful for most cancer types. Thus the unique activities in modulating caveolae and lipid rafts for a subset of platinum(IV) compounds identifies specific therapeutic applications for cancers—such as multiple myeloma (Podar, 2006)—different from the indiscriminate DNA-alkylating actions of platinum(II)'s currently in use.
Interactions with caveolae have also been noted for other metals and compounds. Ferrous (Fe(II)), but not ferric (Fe(III)), iron is capable of modulating key cellular signaling proteins by interacting with caveolae (Chen, 2007). Arsenic(III) has also recently been reported to induce increased caveolae/caveolin expressions (Straub, 2007), although the mechanism for this is not clear. Pervanadate and vanadate have both been reported to alter caveolae functions in endothelial cells (Aoki, 2007), while orthovanadate altered caveolin-2 proteins, leading to changes in caveolar activity (Botos, 2007). While no publications appear to identify selenium in caveolae, its activities oppose those of a known caveolae inhibitor, phorbol 12-myristate 13-acetate (lyengar, 2005), while acting upon proteins known to interface with caveolins (Park, 2007) and thus imply the possibility of another active subgroup of metals affecting caveolae.
Caveolin-1 is one of three known caveolin proteins found in caveolae and in lipid rafts, and is a major decision point in cellular functions. Loss of caveolin-1 function is related not only to certain types of cancer, but to many other human diseases, including those of immune dysfunction, pathogenic infections, diabetes, cardiovascular diseases, and others (Thomas 2008; Cohen 2004; Cohen 2003).
Caveolae, Lipid Rafts, and Caveolins
Lipid rafts are ordered membrane lipid microdomains containing glycosphingolipids and cholesterol. They are characterized (as are caveolae) by their insolubility in cold nonionic detergents. Their involvement in cellular processes is highlighted not only by the co-localization of numerous regulatory proteins, but by the widespread presence of these structures across mammalian cell types. Studies indicate that the plasma membrane is maintained by an active cytoskeleton, whereby the membrane raft hypothesis proposes specific lipids may dynamically associate to form platforms for membrane protein sorting and formation of signaling complexes (Simons, 1997). Their association with membrane receptors involves them in cellular activation and transformation processes, immune synapses (Langlet, 2000), and transport processes.
Caveolae include a number of detergent-insoluble 50-100 nm compositions within a cell membrane, detached vesicles, the Golgi apparatus, endoplasmic reticulum, mitochondria, and other organelles. These may take the form of rafts, tubules, grapes, or vesicular invaginations, composed of sphingolipids, phospholipids, cholesterol, and proteins. The key distinction between caveolae and lipid rafts is the presence of oligomeric caveolin proteins in the former—three, plus their isoforms have been identified—although caveolin proteins also associate in lipid rafts preceding assembly (Hurtado, 2008). Like lipid rafts, caveolae are profoundly involved in human health and diseases (Benarroch, 2007; Michel, 2007; Patra, 2007). In the presence of caveolin proteins, flask or tear-shaped structures are most prevalent, and these tend to be associated with fully differentiated, mature cells. In contrast, the absence of caveolin results primarily in lipid rafts. Caveolae have been associated with most cell types including endothelial and muscle cells, adipocytes, lung epithelial and glial cells, and astrocytes. Of particular significance, they are also present in effector cells of the immune system, including neutrophils, macrophages, mast cells, and dendritic cells (Ohnuma, 2007; Li, 2005; Harris, 2002; Werling, 1997); although some studies identify caveolae-related domains (devoid of caveolin proteins) in hematopoietic cells (Parolini, 1999). Important to vision and retinal diabetes, caveolin proteins and caveolae have been identified in the retina (Berta, 2007). In some cases, caveolin were detected to associate in plasmalemmal and vesicular caveolae (Liu, 2002; Cohen, 2004; Williams, 2004).
The three caveolin proteins (21-24 kD), caveolins-1, -2, and -3, may form homodimers, heterodimers (caveolin 1/2), or larger oligomeric assemblies. Caveolin-1 is the most prevalent of these, being found in most cells, while caveolin-3 had formerly been thought to be restricted to only muscle and heart cells, but is now also recognized to be found in glial cells (Ikezu, 1998; Silva, 2007). Caveolin-2 has been previously described to require caveolin-1 (Parolini, 1999), but its expression and localization within lipid droplets (Fujimoto, 2001) may suggest unique functions; caveolin-2 may also be indicative of basal-like carcinomas (Savage, 2007). Known caveolin functions include lipid and membrane trafficking, membrane structure, and signal transduction. Caveolin-1 is considered fundamental to cholesterol transport (Ikonen, 2004).
Signaling Domain
Caveolae are known to serve as organizational locations for association of intracellular signal transduction proteins (Isshiki, 2002). A growing number of key regulatory proteins have been shown to associate with caveolin-1 through its scaffolding domain (residues 82-101), identified by either sequence *xxxx*xx* or *x*xxxx* (where *=an aromatic residue—tryptophan, phenylalanine or tyrosine and x=any other residue), located in the juxtamembranous region of the N-terminal domain (Couet, 1997). This is part of the “caveolin-1 scaffolding domain hypothesis” (Okamoto, 1998). A partial list of signaling molecules containing this motif and shown to associate with caveolin proteins include: G proteins; Ha-Ras, cNeu and s-Src/Fyn (Src family kinases); endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), tyrosine kinase A (TrkA); protein kinase C(PKC); mitogen-activated protein kinase extracellular signal-regulated kinase cascade (MEK/ERK) (Engelman, 1998); protein kinase A (PKA); alkaline phosphatase; phosphofructokinase as well as receptors endothelial growth factor receptor (EGFR); platelet derived growth factor receptor (PDGFR); p75 nerve growth factor receptor (NGFR); estrogen receptor; androgen receptor (Cohen, 2004; Park, 2005); Erb B receptors (Dobrowsky, 2005); transforming growth factor beta receptors (TGFR) types one and two (Santibanez, 2008); vitamin D receptor (Norman, 2006); insulin receptor (Ishikawa, 2005) and others. Caveolins may categorically inhibit kinases (Couet, 1997), since the scaffolding binding motif is contained within a highly conserved subdomain IX of both tyrosine and serine/threonine kinases. Interestingly, the interaction of signaling proteins with caveolin is predominantly a negative regulation, disallowing constitutive activations often associated with cell transformation, viral infection, and cancer.
Trafficking and Transport
Another function of caveolae is endocytotic trafficking. Broadly, there are two mechanisms for endocytosis—those of clathrin-coated pits and those of caveolae. The former mechanism typically includes fusion with lysosomes, where content degradation occurs. The latter appears to bypass lysosomal processes, routing directly to the endoplasmic reticulum (e.g., cholesterol) (Anderson, 1998) or nucleus (i.e., hormones) (Hirata, 2007). Extracellular molecules, ions, and proteins may employ various caveolae-mediated transducers (“transcytosis”) to gain functional access to intracellular sites (Ortegren, 2007). This sequence is suspected of transporting microorganisms and infectious components (such as proteins) of viral, parasitic and bacterial diseases and is evidenced by examples of Escherichia coli accessing mast cells (Shin, 2001) or Newcastle disease virus infection of host cells (Cantin, 2007), among others. Associations between GPI (glycosylphosphatidylinositol) anchors, extracellular domains, and caveolae may serve as docking sites for cognate receptors facilitating this uptake, while some pathogens may express lipid rafts themselves, participating in infectivity (Campbell, 2004).
Yet another function of caveolae involves assembly and cellular export. Budding processes in the assembly of viral components at lipid raft domains have been observed by several investigators (Nguyen, 2000; Campbell, 2001; Ono, 2001). Limited interactions are known at this time, although coexpression of caveolin-1 with HIV-1 was reported to block viral production (Llano, 2002). HIV Gag protein has also been shown to be targeted to the membrane during assembly and release (Ono, 2004). Prions, amyloid and viral proteins utilize lipid rafts to confer protein conformational changes imperative to their activations (Fantini, 2007).
Caveolae and lipid rafts associate with p-glycoproteins which affect drug uptake into cells. Increased caveolin expression can decrease multi-drug resistance mechanisms, facilitating therapeutic treatments (Storch, 2007; Cai, 2004; Lavie, 2001)
Any of the caveolin-scaffolding proteins can be affected by changes in caveolae. For example, Fyn is a src-family tyrosine kinase. It participates in T-cell receptor signaling and adhesion-mediated signaling, and demonstrates functionalities in fyn (−/−) mice that have myelin defects (Resh, 1998). Decreased caveolin protein functionality would therefore be expected to affect fyn protein activities, for example.
Oncogenesis and Tumor Growth
Caveolin-1 has been associated with cell transformation, oncogenesis, and metastasis, and has been identified as a candidate tumor suppressor (Fiucci, 2002; Wiechen, 2001; Capozza, 2003). Caveolin-1 is often mutated in breast cancer (Lee, 2002), with several isoforms attributed to disease-related dysfunction. Caveolin-1 null mice (Cav-1 (−/−)) showed a 10-fold increase in tumor incidence, a 15-fold increase in tumor number per mouse (multiplicity), and a 35-fold increase in tumor area per mouse, as compared with wild-type littermates following a 16-week exposure to dimethylbenzanthracene (Capozza, 2003). Thus, gene expression of Cav-1 may protect against oncogenesis in certain tumors.
Metastasis
Ras-homology-subfamily GTPases (guanine triphosphate hydrolase enzymes) are involved in actin cytoskeleton rearrangement during cell migration; RhoC GTPase is associated with highly aggressive and metastatic tumors (del Peso, 1997). Along with other Rho-subfamily members, this GTPase contains a caveolin-1 binding domain. In pancreatic adenocarcinomas, caveolin-1 negatively regulates RhoC activation and inhibits cellular migration/invasion associated with metastasis (Lin, 2005).
Many tumors show loss of caveolin-1 expression; when re-expressed, cells lose anchorage-independent mechanisms of growth (Engelman, 1997). Growth of normal cells proceeds through signaling pathways such as Erk (extracellular signal-related kinase), Phosphoinositol kinase (PI3-K), and Rac (a GTPase) that require integrin-mediated cell adhesion, and are therefore, anchorage-dependent. Loss of anchorage-dependent growth is associated with tumor growth and metastasis (Fiucci, 2002). Integrin-mediated cell adhesion binding sites are located within caveolae and transport is facilitated by caveolin-1. In the absence of caveolin-1, GM1 ganglioside remains on cell surfaces where Rac, Erk and Akt (serine-threonine kinase) lose their adhesion-dependence and regulation. Basal GM1 internalization appears to proceed through multiple endocytotic pathways but studies show that internalization induced by detachment is specific to caveolae and caveolin-1 (del Pozo, 2005). These mechanisms demonstrate a role for caveolin-1 in suppression of anchorage-independent growth.
Downregulation of both MMP-2 and MMP-9 (Williams, 2004) have recently been associated with increased presence of Cav-1. These matrix metalloproteinases (MMPs) are also related to loss of anchorage-independent growth, or metastatic potential, as observed in mammary and lung models. MMPs degrade extracellular matrices critical to cell migration, participate in cell proliferation and angiogenesis.
Receptors
The epidermal growth factor receptor (EGFR) is overexpressed in several types of cancer. Under oxidative stress, EGFR is aberrantly phosphorylated by Src kinase and localizes with caveolin-1 to the plasma membrane; later, it transports via caveolar endocytosis to a perinuclear compartment in an active state. This leads to prolonged activation of the receptor and relates to oncogenic potential (Khan, 2006).
EGFR and HER2, ErbB family transmembrane receptor tyrosine kinases, and their ligands are consistently implicated in human (and rodent) breast cancers, including invasive ductal carcinoma of the breast. Additionally, estrogen and progesterone receptors associate with caveolin-1 (Park, 2005). Both receptors are negatively regulated through their interaction with the caveolin-1 scaffolding domain (Okamoto, 1998).
Tumor necrosis factor receptor-1 (TNFR-1) has been shown to be related to caveolae. In cells deficient of lipoproteins, and thus low in membrane cholesterol, reduced cell surface expression of TNFR-1 and CD36 were observed in conjunction with the absence of caveolae. Since TNF-alpha mediates apoptosis, without TNFR-1, this apoptotic pathway can be blocked (Ko, 1999). Thus caveolae mediate cell surface receptors affecting cellular apoptosis.
In adipocytes, insulin reception is directly linked to caveolin-1. Tyrosine phosphorylation is specific for insulin and can be blocked by reducing cholesterol content in the membrane (with beta-methyl-cyclodextrin), essentially eliminating functional caveolae. Metabolic changes, altered free fatty acid and triglyceride levels, and decreased leptin in caveolin-1 null (−/−) mice are similar to prediabetic conditions in humans. Cav-1 null mice also express 90% fewer insulin receptors in adipose tissue (Cohen, 2004). Regulation of caveolin-1 expression is considered an important mechanism for insulin sensitivity (Oh, 2006), while caveolae may have fundamental roles in obesity, diabetes and metabolic disorders (Ortegren, 2007).
Cardiovascular Function
Nitric oxide (NO) is a potent chemokine of the vascular system. Two enzymatic producers of this chemokine, eNos and nNos, contain the scaffolding motif. Reduction of a broad range of inflammatory cytokines through caveolar control such as macrophage inflammatory proteins and monocyte chemoattractant proteins as well as vascular cell adhesion molecule (VCAM-1), cholesterol and fatty acid transport, Interleukin (IL)-6, IL-10, cluster of differentiation (CD)40, and haptoglobin may reduce a broad range of cardiovascular diseases. Caveolin-1-null mice develop cardiac disease similar to hypertrophic cardiomyopathy in humans (Frank, 2004; Cohen, 2003).
Diabetes
Adipocytes are currently known to express the greatest number of caveolae. Given the direct interaction between the insulin receptor and caveolin proteins, as well as effective localization of at least two insulin-responsive elements to caveolae (insulin receptor and GLUT4), a role of caveolae in diabetes as well as metabolic regulation is likely to provide therapeutic utility (Cohen, 2003). Membrane-localized caveolin-1 protein is decreased in diabetic kidneys. Diabetes-mediated alterations in eNOS (endothelial nitric oxide synthase) and caveolin-1 expression are consistent with the view of decreased bioavailability of renal eNOS-derived NO (Komers, 2006). The dissociation of insulin receptor from caveolin-1 is proposed to cause pathogenic signaling in adipocytes (Kabayama, 2007).
Structure
Two mutations in the human CAV-3 gene result in an autosomal-dominant form of limb-girdle muscular dystrophy; mutations on the CAV-3 gene lead to rippling muscle disease (Cohen, 2004). Caveolin-1 is also critical to liver proliferation, lipogenesis, liver regeneration, and lipid metabolism (Frank, 2007; Mayoral, 2007; Fernandez, 2006).
Immunological Response and Antigen Presentation
Cells of the immune system arise from pluripotent stem cells through two main lines of differentiation, the lymphoid lineage and the myeloid lineage. The lymphoid lineage produces lymphocytes, such as T cells, B cells, and natural killer cells, while the myeloid lineage produces monocytes, macrophages, and neutrophils and other accessory cells, such as dendritic cells, platelets, and mast cells. Lymphocytes circulate and search for invading foreign pathogens and antigens that become trapped in secondary lymphoid organs, such as the spleen and lymph nodes.
Antigens are taken up by antigen-presenting cells (APCs). The interaction between T cells and APCs triggers several effector pathways, including activation of cytotoxic T lymphocytes (CTLs) and stimulation of T cell production of cytokines. Major histocompatibility compound (MHC) molecules present antigens on the cell surface of antigen-presenting cells. Cytotoxic T lymphocytes then recognize MHC molecules and their associated peptides and attack the associated target cell. Antigens are processed according to their origin—intracellular or extracellular. Intracellular antigens are presented by class I major histocompatability (MHC) molecules to CD8+ cytotoxic T lymphocytes, effector cells derived from pluripotent stem cells of lymphoid lineage. These are important in resisting pathogens and cancer, and allograft rejection. A distinct route for extracellular antigens use class II MHC molecules, presented to CD4+ helper T cells on the cell surface of APCs such as macrophages.
Caveolae were not originally attributed to cells or lymphatic origin, but this view has changed in the last decade. They have since been identified in human, murine, and bovine neutrophils, macrophages, mast cells, lymphocytes, and antigen-presenting cells (APC) (Harris, 2002; Li, 2005; Ohnuma, 2007). Now, the fundamental role of caveolin proteins and caveolae for immunological response is becoming clearer. For instance, caveolin-1 has been identified to activate thymus cells (T-cells) through the cell surface glycoprotein CD26, leading to activation of nuclear factor kappa beta (NF kappa beta) and T-cell proliferation (Ohnuma, 2007). The mechanism includes upregulation of CD86 expression, a guanylate-kinase-like molecule, CARMA1 and I kappa beta kinase (IKKbeta). CD26, preferentially expressed on the CD4+ memory T-cell subset, binds to caveolin-1 on APCs through the caveolin-scaffolding domain (Ohnuma, 2004). Caveolin-1 has been reported to act as a potent immunomodulatory molecule in macrophages (Wang, 2005). Recent hypotheses also emphasize the critical role of lipid rafts in “immunsynapses” between APCs and T-cells; APCs and B-cells; and B-cells with T-cells (Dustin, 2001; Bromley, 2001). Caveolae and lipid rafts participate in antigen-presentation (Khan, 2007; Sigal 2004; Werling 1999). Hence, these are identified as possible targets of immune-modulation and of immunotherapy (Matko, 2002).
Macrophages are now known to express caveolin-1 (Li, 2005). Loss of caveolin-1 impairs macrophage phagocytosis in Cav-1 knockout mice, suggesting a role in innate immunity, regulation of inflammatory responses and development of autoimmune disease.
Activated Helper T-cells proliferate and secrete a variety of interleukins. However, inadequately-activated T-cells, receiving only one signal in the absence of co-stimulation, become anergized, leading to tolerance (Mueller, 1995).
Murine splenic B-lymphocytes (bone-derived) express caveolin-1. Their activation is dependent upon a Tec family tyrosine kinase known as Bruton's tyrosine kinase (Btk). This kinase has a caveolin-1 scaffolding domain which, when obstructed, prevents B-cell development, differentiation and signaling (Vargas, 2002). Bmx is a human Tec family tyrosine kinase also containing the scaffolding domain.
Two of the most highly expressed Src-family nonreceptor protein tyrosine kinases are p53/p56lyn and p56Ick. Both are involved in the transduction of signals for proliferation and differentiation of monocytes, B-lymphocytes and T-lymphocytes (thymus-derived), respectively. These have been identified in low-density Triton-insoluble caveolar-like subfractions in leukemic cell lines and granulocytes. Other factors identified in the same subfractions include src (rous sarcoma-like kinase), hck (hemopoietic cell kinase), CD4, CD45, G-proteins, and CD55. These observations lead to the hypothesis for a role of these vesicles in signal transduction mechanisms for hemapoietic cells (Parolini, 1996).
HIV and Other Pathogens
Myristoylation is a signature of caveolar-directed proteins, including Nef protein—present in both HIV and SIV (human and simian immunodeficiency viruses). It is no great surprise to learn that viral proteins seek to hijack cellular signaling, including transduction pathways, associated with caveolar scaffolding. Viruses deficient in functional Nef fail to establish high viral loads or progress into disease. Additionally, Nef protein is sufficient to cause AIDS-like symptoms, and leads to production of inflammatory cytokines which further fuel viral replication and infection (Olivetta, 2003; Hanna, 2006). Downmodulation of both CD4 and MHC1 (major histocompatability-1) result from distinctive endocytotic rerouting in the presence of Nef (Marsh, 2000). Loss of CD4 exposes a cell to reinfection; loss of MHC1 prevents antigen-presentation by the infected cell to the immune system.
Of great significance, Hovanessian et al. (2004) identified a conserved caveolin-1 binding domain in gp41 (glycoprotein-41) of HIV-1, HIV-2, and SIV. Both gp120 and gp41 are viral transmembrane envelope glycoproteins that interact with CD4 and a chemokine receptor to gain viral entry into permissive cells. The binding motif 623WNNMTWMEW631 preferentially uses W over F or Y in all of the 862 HIV-1 isolates from most of the HIV clades (Dong, 2001). Immunoprecipitation of gp41 from HIV-infected MT4 cells produced a gp41/caveolin-1 compound, confirming direct interaction during infection. Furthermore, development of a vaccine using a 16-residue synthetic peptide to this gp41 region in rabbits led to inhibition of HIV-1, but not HIV-2, infectivity in primary CD4+ T-lymphocytes (Rey-Cuille, 2006). Clearly, the interaction of virus with caveolin-1 is critical to infectivity.
Pathogenic endocytosis through cellular caveolae is proposed to relate to the localization of their cognate receptors within caveolae of the host cell (Shin, 2001). Pathogens currently identified using this pathway include, but are not limited to: Escherichia coli, Vibrio cholerae toxin, Simian Virus 40, respiratory syncytial virus, Newcastle disease virus (Cantin, 2007), Japanese encephalitis virus, Echovirus 7, Enterovirus 70, Marburg and Ebola viruses (Bavari, 2002); Mycobacterium bovis, Campylobacter jejuni, Toxoplasma gondi, Plasmodium falciparum, Chlamydia trachomatis, Mycobacterium kansasii, pneumocustis carinii, Toxoplasma gondii, Clostridium septicum toxin, Enterobacterial lipopolysaccharide, Aeromonas hydrophila toxin, Helicobacter pylori toxin and Scrapie prion protein.
Some pathogens are known to assemble within caveolae or lipid rafts. Budding and export are linked with vesicular transport and localize pathogens to vital resources such as cholesterol and signaling pathway proteins. Examples of pathogens currently identified include, but are not limited to: HIV (Nguyen, 2000; Campbell, 2001; Holm 2003); Semliki Forest virus (Lu, 2000); Measles virus (Manie, 2000) and prions (Taylor, 2006).
AIDS (auto immune deficiency syndrome) is characterized by abnormal cytokine levels including interleukin-6 (IL-6); inflammatory protein-10 (IP-10); interferon-gamma (IFN-gamma); and IL-10; as well as monocyte chemoattractant proteins (MCPs); macrophage inflammatory proteins (MIPs); matrix metalloproteinases (e.g., MMP-9 and -2) (Webster, 2006; Kumar, 1999; Conant, 1999); vascular endothelial growth factor (VEGF) and others. These factors have been associated with immunological malfunction, virus-infected cell migration, dementia (leading cause of HIV-1 related death), infection and progression of disease. Cytokines affect production of HIV-1 from primary mononuclear phagocytes (Koyanagi, 1988). Reducing overexpression of select cytokines, such as using MMP inhibitors, have inhibited HIV-associated symptoms such as neurotoxicities (Johnston, 2001).
Cancers of Viral Origin
An estimated 30% of cancers have viral origins, some of which are listed in Table 1.
TABLE 1Cancers of Viral OriginVirusType of CancerEpstein-Barr virus (EBV)Burkitt's lymphomaNasopharyngeal carcinomaB-cell lymphomaHodgkin's diseaseBreast cancer (suspected)Hepatitis B virus (HBV)Liver cancerHepatitis C virus (HCV)Splenic lymphomaLiver cancerHuman herpesvirus-8 Kaposi's sarcoma(HHV-8)Primary effusion lymphomaMulticentric Castleman diseaseHuman papillomavirus Cervical, vulvar, vaginal, penile, (HPV)anal, skin oropharyngealHuman T-cell lymphotrophic Adult T-cell leukemia/lymphomavirus type 1 (HTLV-1)Simian virus 40 (SV40)MesotheliomaNon-Hodgkin's lymphoma, brain and bone tumors, and B-cell lymphomas (suspected)